EP0261577B1 - Dicarbonsäurediamide, Verfahren zu deren Herstellung, diese enthaltende ionenselektive Membranen und Testvorrichtungen, sowie Lithiumkomplexe der Dicarbonsäurediamide - Google Patents

Dicarbonsäurediamide, Verfahren zu deren Herstellung, diese enthaltende ionenselektive Membranen und Testvorrichtungen, sowie Lithiumkomplexe der Dicarbonsäurediamide Download PDF

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Publication number
EP0261577B1
EP0261577B1 EP87113553A EP87113553A EP0261577B1 EP 0261577 B1 EP0261577 B1 EP 0261577B1 EP 87113553 A EP87113553 A EP 87113553A EP 87113553 A EP87113553 A EP 87113553A EP 0261577 B1 EP0261577 B1 EP 0261577B1
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EP
European Patent Office
Prior art keywords
formula
dicarboxylic acid
chain
ion
groups
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Expired - Lifetime
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EP87113553A
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German (de)
English (en)
French (fr)
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EP0261577A1 (de
Inventor
Simon Wilhelm
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WILLI MOELLER AG
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Moller Willi Firma
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/333—Ion-selective electrodes or membranes
    • G01N27/3335—Ion-selective electrodes or membranes the membrane containing at least one organic component
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/20—Manufacture of shaped structures of ion-exchange resins
    • C08J5/22—Films, membranes or diaphragms
    • C08J5/2206—Films, membranes or diaphragms based on organic and/or inorganic macromolecular compounds
    • C08J5/2275—Heterogeneous membranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2377/00—Characterised by the use of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Derivatives of such polymers
    • C08J2377/10—Polyamides derived from aromatically bound amino and carboxyl groups of amino carboxylic acids or of polyamines and polycarboxylic acids

Definitions

  • the present invention relates to new dicarboxylic acid diamides, the amine component of which is dicyclohexylamine. These form lithium complexes that are soluble in the lipophilic solvent.
  • the dicarboxylic acid diamides have a high selectivity for lithium ions in comparison to other alkali metal ions and alkaline earth metal ions.
  • the dicarboxylic acid diamides can be used as an ion-selective component in ion-selective membranes for determining the concentration of lithium ions and also in test devices, for example test strips, for determining lithium ions in liquid media.
  • the present invention relates to a process for the preparation of the new dicarboxylic acid diamides.
  • dicarboxylic acid diamides which form lipophilic complexes with cations and which can be used as components of ion-selective membranes for determining the concentration of the cations in question have already been described in the literature.
  • dicarboxylic acid diamides described so far are also those which have a certain selectivity for lithium ions compared to other alkali metal ions.
  • dicarboxylic acid diamides which have a lithium selectivity.
  • the amide-forming amine component of these dicarboxylic acid diamides is a dialkylamine in which one of the two alkyl groups is unsubstituted and the other of the two alkyl groups is substituted with alkoxy groups, acyl groups, ester groups or amide groups.
  • Lithium complexes of these dicarboxylic acid diamides were administered to rats by intracerebral injection and, as a result, a higher concentration of lithium ions could be achieved in the cortex of these animals compared to a corresponding administration of lithium chloride.
  • the concentrations of the most important cations found in biological fluids namely Na + , K + , Ca 2+ and hydrogen ions can easily be determined in clinical laboratories by using electrodes equipped with an appropriate ion-selective membrane.
  • the test for lithium ions is still carried out according to the method of flame photometry or atomic absorption spectrometry.
  • the determination of the concentration of lithium ions in the blood serum is very important when patients suffering from manic-depressive psychoses are treated with lithium ion therapy or when lithium ions are administered prophylactically to patients in order to prevent the occurrence of manic-depressive psychoses.
  • A. Amidsen and M. Schou in Münch. Med. Wienschr. 117 (1975) 1417 and A. Amidsen, Dan. Med. Bull., 22 (1975) 277.
  • an ion-selective membrane which is used in an electrode to determine the activity of the lithium ions in the blood serum is a high selectivity coefficient for lithium ions compared to other alkali metal ions and especially necessary when compared to sodium ions.
  • An ion-selective component of an ion-selective / ive membrane for the determination of lithium ions in body fluids must therefore meet high requirements with regard to its Li + / Na + selectivity.
  • electrodes which are equipped with such lithium-selective membranes must have adequate stability of the electrode potential and the membranes must also have a sufficiently long service life if they are brought into contact with blood serum or whole blood during the determination.
  • lithium-selective components which are dicarboxylic acid diamides are already described.
  • the amide-forming amine of these dicarboxylic acid diamides is a substituted di-heptylamine in which the heptyl groups can carry aliphatic ethers, tetrahydrofuran, esters and amides as substituents.
  • the selectivity coefficient of these compounds for lithium ions over sodium ions is at best only 13, which makes it impossible to determine the concentration of lithium ions in the presence of a higher concentration of sodium ions.
  • Electrodes which have an ion selective membrane and which contain dicarboxylic acid diamides which have a selectivity for lithium ions over sodium ions are described in the publication by AF Zhukov, D. Erne, D. Amman, M. Güggi, E. Pretsch and W. Simon in Analytica Chimica Acta, 131 (1981) on pages 117-122.
  • European Patent Publication No. 0 174 572 describes two cyclohexane-1,2-dicarboxylic acid diamides, which of the known compounds had the highest selectivity coefficient for lithium ions compared to other alkali metal ions. These compounds correspond to structure A above, with the rest of the formula has the structure given above while grouping the formula either the formula or the formula having.
  • Ion-selective membranes which contain one of the two cyclohexane-1,2-dicarboxylic acid diamides described in European Patent Publication No. 0 174 572 as ion-selective component and also contain o-nitrophenyl-n-octyl ether as plasticizer, have a high selectivity for lithium ions over sodium ions , a value for
  • lithium ions in physiological liquids such as blood serum or whole blood can be determined , but the corresponding membranes have a lifespan of only a few weeks if they are frequently in contact with blood serum or whole blood.
  • the aim of the present invention was to develop new dicarboxylic acid diamides which have a high selectivity for lithium ions compared to other alkali metal ions and which make it possible to produce corresponding ion-selective membranes which have a long service life when in contact with test solutions, in particular biological liquids such as for example blood serum.
  • dicarboxylic acid diamides which differ in their chemical structure very clearly from the most advantageous lithium-selective carboxylic acid amides known to date, namely the two cyclohexane carboxylic acid diamides described in European Patent Publication No. 0 174 572, have a very high selectivity for Show lithium ions compared to sodium ions and that with the help of these new dicarboxylic acid diamides, lithium-selective membranes can be produced which have a long lifespan even if they come into frequent contact with blood serum and whole blood.
  • the present invention therefore relates to the dicarboxylic acid diamides, which are characterized in that they have the formula in which formula I the radicals R independently of one another have the meaning of hydrogen atoms, branched-chain or straight-chain alkyl radicals having 1 to 20 carbon atoms, branched-chain or straight-chain alkenyl radicals having 2 to 20 carbon atoms or branched-chain or straight-chain alkynyl radicals having 2 to 20 carbon atoms.
  • Preferred dicarboxylic acid diamides of the formula I are those in which the radicals R independently of one another have the meaning of hydrogen atoms or straight-chain or branched-chain alkyl radicals having 1-15 carbon atoms, preferably hydrogen atoms or straight-chain or branched-chain alkyl radicals having 1-8 carbon atoms.
  • the radicals R preferably at least two of the radicals R have the meaning of hydrogen atoms and particularly preferably three to six of the radicals R have the meaning of hydrogen atoms.
  • a dicarboxylic acid diamide was tested which has the same basic structure as the dicarboxylic acid diamide of the formula II given above, but in which the amide-forming amine component is not dicyclohexylamine but methyl-heptylamine.
  • This acid amide for comparison purposes thus has the following formula B. B on.
  • the compound of the formula B and other dicarboxylic acid diamides, the dicarboxylic acid residue of which is identical to that of the inventive dicarboxylic acid diamides of the formulas 111, V and VI, but in which the amide group of the dicarboxylic acid diamide derives from methyl-heptylamine, are described in the publication by Zhukov et al.
  • the CH 2 group of the corresponding acetic acid amide of formula VIII or acetic acid ester of formula IX must be sufficiently activated by the removable group X so that etherification with the hydroxyl groups of the diol of formula VII takes place .
  • An example of a suitable ester of the formula IX is a corresponding diazoacetic acid ester, for example ethyl diazoacetic acid.
  • the dicarboxylic acid diamides of the formulas 11-VI were prepared by the process described above.
  • Another object of the present invention are lithium complexes of the dicarboxylic acid diamides of the formula 1, which are characterized in that they are 1: 1 complexes of a lithium ion and a molecule of the complexing agent of the formula 1.
  • the X-ray structure analysis of these lithium complexes showed that the complexes are 1: 1 complexes, ie 1 lithium ion is complexed by 1 molecule of the complexing agent.
  • the crystal structure of the LiNCS complexes with the complexing agent of formula II was investigated. It was found that the four oxygen atoms of the complexing agent, namely the two ether oxygen atoms and the two carbonyl oxygen atoms of the carboxylic acid diamide, form the base of a slightly deformed square pyramid, the Li + cation being 0.76 angstroms above the base of the pyramid and this lithium cation being the base Nitrogen atom of the NCS anion is bound. In this complex, the average distance between the lithium ion and the carbonyl oxygen atom is 1.94 A while the average distance between the lithium cation and the ether oxygen atom is 2.16 A.
  • the complexing agents of the formula I according to the invention have a significantly higher selectivity for lithium ions compared to sodium ions than that in the lite mentioned above
  • Complexing agents described that differ from the compounds of the formula I according to the invention only in the amine component of the acid amide According to the results of the investigations of the crystal structure, it would be far more likely that the amine component of the carboxylic acid diamides has a significantly smaller influence on the Li / Na selectivity.
  • Another object of the present invention is an ion-selective membrane for determining the concentration of lithium ions, which is characterized in that it contains an inventive carboxylic acid diamide of the formula as an ion-selective component.
  • Preferred ion-selective membranes according to the invention also contain poly (vinyl chloride) as a matrix for the ion-selective component.
  • the ion-selective membranes according to the invention also contain a plasticizer.
  • Lipophilic plasticizers are preferred as plasticizers, and especially preferred plasticizers are esters of organic carboxylic acids.
  • ion-selective membranes using poly (vinyl chloride) as the carrier and the dicarboxylic acid diamides of the formula I according to the invention were able to be produced which, when used for a long time, to determine lithium concentrations in blood serum and whole blood, lifespan of many months.
  • the above-mentioned ion-sensitive membranes preferably contain 1.2% by weight to 2.0% by weight, based on the total weight of the membrane, of the ion-selective dicarboxylic acid diamide of the formula I.
  • the reference electrode was a saturated calomel electrode with two serial diffusion potential transitions and a free liquid transition of 1 ul / h.
  • a 0.001 molar LiCI solution was used as the electrode filling solution, and for more details on the implementation of the measurements and also the mathematical evaluation of the results, reference is made to the publication by E. Metzger, D. Ammann, R. Asper, W. Simon, in Anal. Chem. 1986, 58, 132.
  • the ion-selective mini-electrode was equipped with a small electrode body made of poly (methyl methacrylate) with a vertical channel with an inner diameter of 0.8 mm.
  • the sample solution could be injected from above into this vertical channel.
  • the channel filled with the sample was brought into contact with the ion-selective membrane and the other side of the ion-sensitive membrane was brought into contact with the electrode filling solution using a silver wire coated with silver chloride as an internal lead.
  • a solution of 0.001 M LiCl plus 0.14 M NaCl plus 0.5% agar-agar was used as the electrode filling solution.
  • the reference electrode was a common macro electrode, as described in the above publication, but equipped with a thin glass tip. The comparison electrode was immersed from above into the electrode channel of the ion-selective mini electrode.
  • the sample solutions were injected with a glass injection syringe and removed after the measurement with vacuum.
  • the sample channel had a capacity of 0.1 ml. After the injection of a sample solution, the measurement was carried out for 4 minutes by determining the EMF values at intervals of 20 seconds.
  • the ion selective membranes were made by the method described by Anker, P .; Wieland; E .; Ammann, D .; Dohner, R .; Asper, R. and Simon, W. in Anal. Chem. 1981, 53, 1970 is described by using a compound of the formula I as an ion-selective component or a compound for comparison purposes as an ion-selective component and also using polyvinyl chloride as the base material and optionally also one of the plasticizers mentioned above and those mentioned above other components used.
  • the ion sensitive membranes were mounted in Philips IS 560 electrode bodies (N.V. Philips, Eindhoven, NL) and the electrodes conditioned in about 2 ml of the electrode filling solution overnight before being used.
  • Another object of the present invention are test devices for the determination of lithium ions which contain as a component a dicarboxylic acid diamide of the formula I according to the invention.
  • Test strips for determining the concentration of ions which contain an ion-selective component are described in European patent publication 0 153 641.
  • test devices according to the invention for example tapes or strips, preferably contain a polymer matrix, e.g. made of polyvinyl chloride.
  • Such test devices preferably additionally contain an indicator which makes it possible to determine a change in the pH value.
  • This indicator can be, for example, one of the customary pH indicators which indicate a change in the pH value due to a color change: if such a test device which contains a dicarboxylic acid diamide of the formula I according to the invention as an ion-selective component with a liquid medium which contains lithium ions is brought into contact, then a complex forms between the lithium ions and the compounds of the formula I according to the invention in this test device. This complexing reaction also changes the pH in the test device and this change in pH can be determined by the response of the pH indicator.
  • test devices for example test strips, enable lithium ions in liquid media, such as body fluids, to be determined quickly and easily.
  • This compound is the compound of the formula VI according to the invention.
  • the mixture was acidified to a pH of about 1 using 6 molar hydrochloric acid.
  • the solvents were evaporated and the residue extracted with acetone.
  • the acetone solution was dried over magnesium sulfate and then the solvent was removed under vacuum.
  • the yield was about 5 g (18 mmol), corresponding to more than 95% of the theoretical yield.
  • the infrared spectrum of the liquid showed peaks at 1805 cm -1 and 1750 cm -1 .
  • the compounds of the formulas II, III, IV and V according to the invention were prepared by the process described in Example 1.
  • the diols required as starting material for the synthesis of the compounds of the formulas II, III and V were obtained from Fluka AG and the diol required for the synthesis of the compound of the formula IV was obtained from Aldrich, Steinheim, FRG.
  • the membranes were produced by the method described in the above-mentioned publication by P. Anker et al. in anal. Chem. 1981, 53, 1970, is described.
  • the poly (vinyl chloride) used was the PVC S704 high molecular weight product, which comes from Lonza AG, Visp, Switzerland, and is now available from Fluka AG.
  • the bis (1-butylpentyl) adipate was used as plasticizer in all membranes, namely the corresponding product purum p.a., which was obtained from Fluka AG.
  • Membranes 1, 2, 3, 4 and 5 are membranes according to the invention.
  • the electrolyte solutions were prepared using water distilled twice in quartz apparatus and the chloride salts used were extremely pure, namely the products purum p.a., or puriss. p.a., Fluka AG, Buchs, Switzerland and pro analysis from E. Merck, Darmstadt, FRG.
  • the blood serum used was obtained from the medical-chemical central laboratory of the University Hospital Zurich, Switzerland.
  • concentrations of sodium ions, potassium ions, the total content of calcium ions and lithium ions were determined by flame photometry or atomic absorption spectrometry. According to this method, a lithium concentration of 0.12 mmUU1 was measured in the blood serum used.
  • small amounts of a solution which contained 0.05 mol of lithium chloride and 0.135 mol of sodium chloride were added to the blood serum. In each case, after the addition of this lithium sodium solution, the serum was mixed for a short time and then sample volumes of 0.1 ml were taken for the determinations.
  • the membranes 1, 2, 3, 4 and 5 according to the invention have a sufficiently high selectivity for lithium, so that with them in the serum samples the lithium concentration in the clinical range of 0.7-1.5 mmol Li + per liter could be determined while a background of 0.14 mol per liter of sodium was present in the corresponding solutions.
  • the membrane for comparison purposes did not have a sufficiently high selectivity for lithium, so that it was no longer possible to determine the lithium concentration in the presence of the stated large amounts of disruptive sodium ions.
  • the membranes 1, 2, 3, 4 and 5 according to the invention were suitable for the quantitative determination of the lithium ions in the serum samples. They were also characterized by great stability of the signals and very quick response. The final EMF value could be measured with these membranes within 20 - 30 seconds.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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EP87113553A 1986-09-23 1987-09-16 Dicarbonsäurediamide, Verfahren zu deren Herstellung, diese enthaltende ionenselektive Membranen und Testvorrichtungen, sowie Lithiumkomplexe der Dicarbonsäurediamide Expired - Lifetime EP0261577B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87113553T ATE52763T1 (de) 1986-09-23 1987-09-16 Dicarbonsaeurediamide, verfahren zu deren herstellung, diese enthaltende ionenselektive membranen und testvorrichtungen, sowie lithiumkomplexe der dicarbonsaeurediamide.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH3795/86A CH668257A5 (de) 1986-09-23 1986-09-23 Dicarbonsaeurediamide, diese enthaltende ionenselektive membranen und testvorrichtungen, sowie lithiumkomplexe der dicarbonsaeurediamide.
CH3795/86 1986-09-23

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EP0261577A1 EP0261577A1 (de) 1988-03-30
EP0261577B1 true EP0261577B1 (de) 1990-05-16

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US (1) US5023374A (es)
EP (1) EP0261577B1 (es)
AT (1) ATE52763T1 (es)
CH (1) CH668257A5 (es)
DE (1) DE3762738D1 (es)
ES (1) ES2004486B3 (es)

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US5750147A (en) 1995-06-07 1998-05-12 Emisphere Technologies, Inc. Method of solubilizing and encapsulating itraconazole
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ATE52763T1 (de) 1990-06-15
ES2004486A4 (es) 1989-01-16
ES2004486B3 (es) 1991-01-01
DE3762738D1 (de) 1990-06-21
US5023374A (en) 1991-06-11
EP0261577A1 (de) 1988-03-30
CH668257A5 (de) 1988-12-15

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